Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt

Marini, Cecilia; Ravera, Silvia; Buschiazzo, Ambra; Bianchi, Giovanna; Orengo, Anna Maria; Bruno, Silvia; Bottoni, Gianluca; Emionite, Laura; Pastorino, Fabio; Monteverde, Elena; Garaboldi, Lucia; Martella, Roberto; Salani, Barbara; Maggi, Davide; Ponzoni, Mirco; Fais, Franco; Raffaghello, Lizzia; Sambuceti, Gianmario

doi:10.1038/srep25092

Cited by 80 publications

(108 citation statements)

References 51 publications

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“…A novel glucose metabolism involving a hexose-6-phosphate dehydrogenase located within the endoplasmic reticulum has recently been identified in multiple cancer cell lines. 55 Since GLUT8 is localized to the endoplasmic reticulum, it may play a role in this process through active hexose transport. The impact of GPR55 inhibition —with ( R,R’ )-MNF or other molecules— in this process and on overall metabolic reprogramming through decreased GLUT8 protein expression will be reported elsewhere.…”

Section: Discussionmentioning

confidence: 99%

GPR55 receptor antagonist decreases glycolytic activity in PANC‐1 pancreatic cancer cell line and tumor xenografts

Bernier

Catazaro

Singh

et al. 2017

Intl Journal of Cancer

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The Warburg effect is a predominant metabolic pathway in cancer cells characterized by enhanced glucose uptake and its conversion to L-lactate and is associated with upregulated expression of HIF-1α and activation of the EGFR-MEK-ERK, Wnt-β-catenin and PI3K-AKT signaling pathways. (R,R’)-4’-methoxy-1-naphthylfenoterol ((R,R’)-MNF) significantly reduces proliferation, survival, and motility of PANC-1 pancreatic cancer cells through inhibition of the GPR55 receptor. We examined (R,R’)-MNF’s effect on glycolysis in PANC-1 cells and tumors. Global NMR metabolomics was used to elucidate differences in the metabolome between untreated and (R,R’)-MNF-treated cells. LC/MS analysis was used to quantify intracellular concentrations of β-hydroxybutyrate, carnitine and L-lactate. Changes in target protein expression were determined by Western blot analysis. Data was also obtained from mouse PANC-1 tumor xenografts after administration of (R,R’)-MNF. Metabolomics data indicate that (R,R’)-MNF altered fatty acid metabolism, energy metabolism, and amino acid metabolism and increased intracellular concentrations of β-hydroxybutyrate and carnitine while reducing L-lactate content. The cellular content of phosphoinositide-dependent kinase-1 and hexokinase 2 was reduced consistent with diminished PI3K-AKT signaling and glucose metabolism. The presence of the GLUT8 transporter was established and found to be attenuated by (R,R’)-MNF. Mice treated with (R,R’)-MNF had significant accumulation of L-lactate in tumor tissue relative to vehicle-treated mice, together with reduced levels of the selective L-lactate transporter MCT4. Lower intratumoral levels of EGFR, pyruvate kinase M2, β-catenin, hexokinase 2 and P-glycoprotein were also observed. The data suggest that (R,R’)-MNF reduces glycolysis in PANC-1 cells and tumors through reduced expression and function at multiple controlling sites in the glycolytic pathway.

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Section: Discussionmentioning

confidence: 99%

GPR55 receptor antagonist decreases glycolytic activity in PANC‐1 pancreatic cancer cell line and tumor xenografts

Bernier

Catazaro

Singh

et al. 2017

Intl Journal of Cancer

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“…Marini et al (49) have estimated NAD + /NADH ratio in 4T1 cell lysates to be~1.7 as compared with NADP + /NADPH ratio of 0.5 using spectrophotometric assay. Wu et al (50) also reported NADPH level in 4T1 lysates to 120 pmol/100 mg proteins as compared with~120 NADP + level.…”

Section: Two-photon Fluorescence Lifetime Imaging Microscopymentioning

confidence: 99%

Two‐photon fluorescence lifetime imaging of intrinsic NADH in three‐dimensional tumor models

et al. 2018

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Most studies using intrinsic NAD(P)H as biomarkers for energy metabolism and mitochondrial anomalies have been conducted in routine two-dimensional (2D) cell culture formats. Cellular metabolism and cell behavior, however, can be significantly different in 2D cultures from that in vivo. As a result, there are emerging interests in integrating noninvasive, quantitative imaging techniques of NAD(P)H with in vivo-like threedimensional (3D) models. The overall features and metabolic responses of the murine breast cancer cells line 4T1 in 2D cultures were compared with those in 3D collagen matrix using integrated optical micro-spectroscopy. The metabolic responses to two novel compounds, MD1 and TPPBr, that target metabolism by disrupting monocarboxylate transporters or oxidative phosphorylation (OXPHOS), respectively, were investigated using two-photon fluorescence lifetime imaging microscopy (2P-FLIM) of intracellular NAD(P)H in 2D and 3D cultures. 4T1 cells exhibit distinct behaviors in a collagenous 3D matrix from those in 2D culture, forming anastomosing multicellular networks and spherical acini in 3D culture, as opposed to simple flattened epithelial plaques in 2D culture. The cellular NAD(P)H in 3D collagen matrix exhibits a longer fluorescence lifetime as compared with 2D culture, which is attributed to an enhanced population of enzyme-bound NAD(P)H in the 3D culture. TPPBr induces mitochondrial hyperpolarization in 2D culture of 4T1 cells along with an enhanced free NAD(P)H population, which suggest an interference with OXPHOS. In contrast, 2P-FLIM of cellular NAD(P)H revealed an enhanced autofluorescence lifetime in 3D 4T1 cultures after MD1 treatment as compared with MD1-treated 2D culture and the control 3D culture. Physical and chemical microenvironmental signaling are critical factors in understanding how therapeutic compounds target cancer cells by disrupting their metabolic pathways. Integrating 2P-FLIM of intrinsic NAD(P)H with refined 3D tumor-matrix in vitro models promises to advance our understanding of the roles of metabolism and metabolic plasticity in tumor growth and metastatic behavior. © 2018International Society for Advancement of Cytometry Key terms NAD(P)H; 4T1; 3D collagen matrix; MD1; TPPBr derivative; two-photon microscopy; FLIM CHANGES in cellular metabolism have long been recognized as a fundamental feature, and are now considered a hallmark, of cancer. A resurgent interest in this area has recently been driven in large measure by significant breakthroughs elucidating relevant mechanisms of cross-talk between not only tumor and stromal cells but also between distinct subpopulations of tumor cells themselves within heterogeneous tumors. In particular, advanced metabolic imaging methods promise to significantly enhance our understanding of how specific microenvironmental factors influence the regulation of cancer cell metabolism on a cell-by-cell basis. Overall, it is becoming clear that a better understanding of the metabolic features of cancer cells-and in particular those that may ...

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“…В недавних исследованиях пока-зано, что метформин реализует свой противоопухолевый эффект через гликолиз и пентозо-фосфатный путь, сни-жая уровень НАДФН [39]. Скорее всего окажется, что мет-формин реализует свое противоопухолевое действие че-рез эффект Варбурга / Кребтри.…”

Section: влияние метформина на энергетический обменunclassified

Metformin as target metabolic drug in oncology

Шатова¹,

Каплун²,

Зинкович³

2017

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Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt

Cited by 80 publications

References 51 publications

GPR55 receptor antagonist decreases glycolytic activity in PANC‐1 pancreatic cancer cell line and tumor xenografts

GPR55 receptor antagonist decreases glycolytic activity in PANC‐1 pancreatic cancer cell line and tumor xenografts

Two‐photon fluorescence lifetime imaging of intrinsic NADH in three‐dimensional tumor models

Metformin as target metabolic drug in oncology

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